The goal of this Program Project Grant is to use a combination of insect and vertebrate systems to understand the origins of the human system of defense against infection. The Principal Investigators have established collaborative interactions which have been highly productive under the auspices of the Human Frontiers in Science Program. Our success results from continual interaction and sharing of expertise that has allowed for novel insights into the field of innate immunity. This Program is an extension and refinement of our collective goal which is to have a real impact on the understanding of innate immunity. To this end, we propose three projects involving six laboratories within four institutions. Project 1 aims to define molecules that are necessary for phagocytosis. Our work on the Drosophila phagocytic receptor croquemort is presented as a platform from which we plan to use Drosophila as a model system to identify genes that are necessary for phagocytosis. The genetic screens described in Project 1 will be complemented by the genetic screens outlined in Project 3. The ultimate goal is to apply this knowledge to mammalian systems in collaboration with Project 2. The goal of Project 2 is a complete analysis of our recent discovery of a human homologue of the Drosophila Toll. This molecule appears to play a pivotal role in linking innate and adaptive immunity in mammalians. Project 3 focuses on two dipteran insects, Drosophila melangaster and Anopheles gambiae. The plan is to identify, characterize and define the model of action of pattern recognition molecules that recognize infectious agents, particularly the protozoans parasite Plasmodium malariae. We propose an Administrative Core that will coordinate communications between investigators and oversee the administration of the grant. We believe that from insects we are able to apply the power of genetic approaches and the unique ability to manipulate responses that cannot be obtained in vertebrates. We plan to use mammalian systems to place this in a context that will impact human disease. This knowledge will provide insights into the links between innate and adaptive immunity which in turn will cast light on pathogen host interactions.